The present invention relates to a novel form of cross-linked high amylose starch and processes for its manufacture. Such cross-linked high amylose starch is useful as an excipient in a controlled-release pharmaceutical formulation when compressed with a pharmaceutical agent(s) in a tablet.
One of the critical factors influencing the rate of absorption of a drug administered as a tablet or other solid dosage form is the rate of dissolution of the dosage form in the body fluids of human or animal.
This factor is the basis for the so-called controlled-release, extended-release, sustained-release or prolonged-action pharmaceutical preparations that are designed to produce slow, uniform release and absorption of the drug over a period of hours, days, week, months, or years. Advantages of controlled-release formulations are a reduction in frequency of administration of the drug as compared with conventional dosage forms (often resulting in improved patient compliance), maintenance of a therapeutic effect over a set period of time, and decreased incidence and/or intensity of undesired side effects of the drug by elimination of the peaks in plasma concentration that often occur after administration of immediate-release dosage forms.
Many systems have been proposed and developed as matrices for the release of drugs. For example, polymeric materials such as polyvinyl chloride, polyethylene amides, ethyl cellulose, silicone and poly (hydroxymethyl methacrylate), have been proposed as vehicles for the slow release of drugs. See U.S. Pat. No. 3,087,860 to Endicott et al; U.S. Pat. No. 2,987,445 to Levesque et al.; Salomon et al., Pharm. Acta Helv., 55, 174-182 (1980); Korsmeyer, Diffusion Controlled Systems: Hydrogels, Chap. 2, pp 15-37 in Polymers for Controlled Drug Delivery, Ed. Tarcha, CRC Press, Boca Raton, Fla. USA (1991); Buri et al, Pharm. Acta Helv. 55, 189-197 (1980).
A substantial need exists for a controlled release composition that can deliver a variety of drugs, both hydrophilic and hydrophobic, in a consistent and reliable manner. Further, this composition should be amenable to all facets of tableting requirements, including, but not limited to, direct compression, appropriate hardness and resistance to friability, and compatibility with the active ingredient(s) contained in the tablet. Also, the composition should be easy to synthesize, biodegradable and non-toxic upon release of the drug.
One of the most widely studied compounds for controlled-release use has been starch, partially because it is biodegradable and is naturally metabolized by the human body [Kost et al., Biomaterials 11, 695-698 (1990)]. Starch has many uses in pharmaceutical products. It can act as a diluent, filler, carrier, binder, disintegrant, coating, thickener, and moisture sink. See U.S. Pat. No. 2,938,901 to Kerr et al., which discloses the use of granular starch cross-linked with sodium trimetaphosphate as a surgical dusting powder; U.S. Pat. No. 3,034,911 to McKee et al., which discloses the use of a cold water swelling and cold water insoluble starch in intact granular form as a disintegrant; U.S. Pat. No. 3,453,368 to Magid, which discloses the use of pregelatinized starches, optionally modified as binders for compressed ascorbic acid tablets; U.S. Pat. No. 3,490,742 to Nichols et al., which discloses a non-granular amylose (at least 50%) obtained from the fractionation of corn starch for use as a binder disintegrant in direct compression and dry granulation tablets; U.S. Pat. No. 3,622,677 to Short et al., which discloses the use of a partially cold water soluble and cold-water swelling starch, derived from a compacted granular starch, as a binder-disintegrant; U.S. Pat. No. 4,072,535 to Short et al., which discloses a pre-compacted starch having birefringent granules, non-birefringent granules, and some aggregates and fragments for use as a binder-disintegrant; U.S. Pat. No. 4,026,986 to Christen et al., which discloses the use of water-soluble starch ethers (e.g., hydroxyalkyl ethers) containing at least 50% amylose for use in forming capsule shells; U.S. Pat. No. 4,308,251 to Dunn et al., which discloses the use of corn, rice, potato and modified starches as an erosion-promotion agent in controlled release formulations prepared by wet granulation; U.S. Pat. No. 4,551,177 to Trabiano et al., which discloses the use of acid- and/or alpha-amylase converted starches as tablet binders; U.S. Pat. No. 4,904,476 to Mehta et al., which discloses the use of sodium starch glycolate as a disintegrant; U.S. Pat. No. 4,818,542 to DeLuca et al., which discloses starch as a biodegradable or bioerodible polymer for porous microspheres possibly coated with a cross-linking agent to inhibit or control drug release; U.S. Pat. No. 4,888,178 to Rotini et al., which discloses the use of starch, preferably maize starch, and sodium starch glycolate as disintegrants in the immediate release of a programmed release Naproxen(copyright) formulation containing immediate release and controlled release granulates in the form of tablets, capsules, or suspension in a suitable liquid media; U.S. Pat. No. 5,004,614 to Staniforth, et al., which discloses the use of starches as pharmaceutical fillers in controlled release devices containing an active agent and a release agent and the use of cross-linked or un-cross-linked sodium carboxymethyl starch for the coating.
U.S. Pat. No. 4,369,308 to Trubiano et al. discloses modified starches which are low swelling in cold water and which are suitable for use as disintegrants in compressed tablets. This is achieved by cross-linking and pregelatinizing in the presence of water, a cold-water insoluble, granular starch, drying the cross-linked, pregelatinized starch if necessary, and then pulverizing the dry starch. No controlled release properties are disclosed or claimed for these starches.
Cross-linked starch has been previously evaluated as a sustained release agent. Visavarungroj et al. [Drug Development And Industrial Pharmacy, 16(7), 1091-1108 (1990)] discloses the evaluation of different types of cross-linked starches and pregelatinized cross-linked starches for their use as hydrophilic matrices. It was determined that cross-linked starches demonstrated a poor swelling power and dispersion viscosity in comparison to pre-gelatinized starch and pregelatinized cross-linked starch. The study concluded that cross-linked modified waxy corn starches, either pregelatinized or not, in comparison to purely pregelatinized waxy corn starch are not suitable to use as a hydrophilic matrix in sustained release formulation.
Nakano et al. [Chem. Pharm. Bull. 35(10), 4346-4350, (1987)] disclose the use of physically modified starch (pregelatinized starch) as an excipient in sustained-release tablets. This article does not mention the specific role of amylose present in starch nor does it even mention amylose.
Van Aerde et al. [Int. J. Pharm., 45, 145-152, (1988)] disclose the use of modified starches obtained by drum-drying or extrusion pregelatinization, particle hydrolysis or cross-linking with sodium trimetaphosphate, as an excipient in sustained-release tablets. Once again, the article does not mention the specific role of amylose present in starch nor does it even mention amylose.
Herman et al. [Int. J. Pharm., 56, 51-63 and 65-70, (1989) and Int. J. Pharm., 63 201-205, (1990)] disclose the use of thermally modified starches as hydrophilic matrices for controlled oral delivery. This article discloses that thermally modified starches containing a low amount of amylose (25% and lower) give good sustained release properties, contrary to high amylose content starches which present bad controlled release properties.
U.S. Pat. No. 3,490,742 to Nichols et al. discloses a binder-disintegrant comprising non-granular amylose. This material is prepared either by fractionating starch or by dissolving granular high amylose starch in water at an elevated temperature. No controlled release properties are disclosed.
U.S. Pat. No. 5,108,758 to Alwood et al. discloses an oral delayed release composition comprising an active compound and glassy amylose. The composition is particularly adapted for achieving selective release of the active compound into the colon. The delayed release is due to a coating. Glassy amylose is one of the two forms of predominantly amorphous amylose, the other being a rubbery form. Here, the glassy amylose delays the release of the active compound from the composition in an aqueous environment but allows its release on exposure to an enzyme capable of cleaving the amylose. The amylose used in this composition is isolated from smooth-seeded pea starch and purified by precipitation from aqueous solution as a complex with n-butanol. The alcohol is then removed from an aqueous dispension of that complex by blowing through a suitable heated inert gas. As aforesaid, the release mechanism is based on an enzymatic reaction. There is no continuous release through the gastrointestinal tractus, but only a delayed release due to the degradation of the coating into the colon. Moreover, it is disclosed that the glassy amylose should preferably not contain hydroxy groups in a derivative form.
European patent application No. EP-A-499,648 to Wai-Chiu et al. discloses a tablet excipient. More particularly, they disclose a starch binder and/or filler useful in manufacturing tablets, pellets, capsules or granules. The tablet excipient is prepared by enzymatically debranching starch with an xcex1-1,6 D-glucanohydrolase to yield at least 20% by weight of xe2x80x9cshort chain amylose.xe2x80x9d No controlled release properties are claimed for this excipient. Moreover, starch (unmodified, modified or cross-linked) must be enzymatically treated with an xcex1-1,6-D-glucanohydrolase to be debranched and to yield the so-called xe2x80x9cshort chain amylosexe2x80x9d. Thus, starch with a high content of amylopectin is obviously preferred and amylose is rejected as not suitable because it is impossible to debranch amylose, since amylose has no branching. The role of amylose is not only ignored but considered negatively.
Mateescu et al. [U.S. Pat. No. 5,456,921] and Lenaerts et al. [J. Controlled Rel. 15, 39-46, (1991)] disclose that cross-linked amylose is a very efficient tool for controlled drug release. Cross-linked amylose is produced by reaction of amylose with a cross-linking agent such as epichlorohydrin, in an alkaline medium. Different degrees of cross-linking can be obtained by varying the ratio of epichlorohydrin to amylose in the reaction vessel. Tablets prepared by direct compression of a dry mixture of cross-linked amylose and a drug swell in solution and show a sustained release of the drug. Depending on the degree of cross-linking of the matrix, different degrees of swelling are obtained. Increasing the degree of cross-linking of amylose first generates an increase of drug-release time, followed by a decrease of drug-release time. The peak drug-release time is observed at a cross-linking degree value of 7.5. A further increase in the degree of cross-linking leads to an accelerated drug release from the cross-linked amylose tablets as a consequence of the erosion process. For cross-linking degree equal or greater than 7.5, increasing the degree of cross-linking of amylose generates a decrease of drug-release time. With degrees of cross-linking above 11, the swollen polymeric matrix presents in vitro disintegration over a period of approximately 90 minutes.
Mateescu et al. [International laid-open patent application No. WO 94/02121] and Dumoulin et al. [Intern. Symp. Control. Rel. Bioact. Mater. 20, 306-307, (1993)] disclose an enzymatically-controlled drug release system based on the addition of xcex1-amylase within the cross-linked amylose tablet. xcex1-amylase is able to hydrolyse xcex1-1,4-glucosidic bonds present in the cross-linked amylose semi-synthetic matrix. Increasing the amount of xcex1-amylase (5 to 25 EU) within the tablets induces a significant decrease in release time from 24 to 6 hours. Hence, drug release is controlled by two sequential mechanisms: (a) hydration and swelling of cross-linked amylose tablets followed by (b) internal enzymatic hydrolysis of the hydrated gel phase.
Cartilier et al. [International laid-open patent application WO 94/21236] disclose powders of cross-linked amylose having a specific cross-linking degree for use as a tablet binder and/or disintegrant. The tablets are prepared by direct compression. The concentration of cross-linked amylose in the tablets is lower than 35% by weight. Degrees of cross-linking from 6 to 30 and more particularly from 15 to 30 are preferred when disintegration properties are required.
U.S. Pat. No. 5,830,884 to Kasica et al. discloses thermally inhibited starches which are used in pharmaceutical products as a diluent, filler, carrier, binder, disintegrant, thickening agent, and coating. They are prepared by dehydrating the starch to a substantially anhydrous or anhydrous state and heat treating the anhydrous or substantially anhydrous starch for a period of time and at a temperature sufficient to inhibit the starch. Starches that are substantially thermally inhibited resist gelatinization and only mimic chemically cross-linked starch.
U.S. Pat. No. 5,879,707 to Cartilier et al. relates to the use of substituted amylose as a matrix for sustained drug release. The sustained release matrix is made of substituted amylose, prepared by reacting in an alkaline medium, amylose, with an organic substituent having a reactive functionality that reacts with the hydroxy groups of the amylose molecule. This substituent is preferably an epoxy or halogen alkane or alcohol. However, only linearly substituted amylose is used and is distinguished from cross-linked amylose which is used in the present invention.
Dumoulin et al. [International laid-open patent application No. WO 98/35992] disclose a process for the manufacture of a slow release excipient consisting mainly of cross-linked amylose having controlled-release properties, for use in the preparation of tablets or pellets. A starch containing a high amount of amylose (high amylose starch) is first subjected to gelatinization. The gelatinized high amylose starch is cross-linked with 1-5 grams of a cross-linking agent per 100 g of dry-based gelatinized high amylose starch in an alkali medium, creating a reaction medium containing a reaction product consisting of a cross-linked high amylose starch slurry. The obtained reaction medium is then neutralized, thereby forming by-products consisting of salts, which are removed from the reaction medium. The recovered cross-linked high amylose starch slurry is then subjected to a thermal treatment at a temperature of at least 60xc2x0 C. and the thermally treated product is dried to obtain the slow-release excipient which contains a substantial amount of impurities.
Lenaerts et al. [J. Controlled Release 53, 225-234 (1998)] have demonstrated that gelatinized cross-linked high amylose starches are useful excipients for the formulation of controlled-release solid dosage forms for the oral delivery of drugs. These excipients exhibit a lack of erosion, limited swelling and the fact that increasing cross-linking degrees results in increase water uptake, drug release rate and equilibrium swelling. These investigators were also able to demonstrate that cross-linked high amylose starch matrices have the lowest inter-subject variability amongst the systems tested and demonstrate a total absence of food effect. Lenaerts et al. were also able to conclude that as the degree of cross-linking increased, the drug would be released faster. The authors concluded that for the gelatinized cross-linked high amylose starch to possess the characteristics needed to have a controlled release of the incorporated drugs, it is necessary that the surface of amylopectin clusters be coated by amylose chemically bound to amylopectin by the cross-linking procedure. This structure is indeed the one obtained by first gelatinizing the high amylose starch to extract amylose from the granules and then carrying out the chemical reaction to chemically bind amylose to the surface of amylopectin clusters, such as when using the process described by Dumoulin et al. in WO 98/35992.
All of the above references which relate to cross-linked high amylose starch teach that the starting amylose material be gelatinized prior to cross-linking. The integrity of starch granules in the dry state is dependent upon the hydrogen bonding between amylopectin and amylose. When an aqueous suspension of starch is heated to a certain temperature, the hydrogen bonding between amylopectin and amylose weakens and the granule swells until collapsing. This process is referred to as xe2x80x9cgelatinization.xe2x80x9d This first step of the process permits leaching of the amylose from the starch granules prior to reaction with a cross-linking reagent, which then creates a cross-linked amylose with controlled-release properties. Moreover, it has been stated that gelatinization of high-amylose starch before cross-linking is required in order to prepare a product possessing the desired controlled-release property. See Dumoulin et al., WO 98/35992.
It has now been surprisingly found that high amylose starch can be subjected to chemical treatment (i.e., cross-linking and hydroxypropylation) in the granular state using very low concentrations of chemical reagent, followed by gelatinization and drying to yield a controlled-release excipient superior in release properties to high-amylose starch excipients produced by a process in which the high amylose starch is subjected to gelatinization as a first step, followed by chemical treatment and drying.
The novel processes, compositions and controlled release activity described herein is counterintuitive to what has been generally known to those skilled in the art. By exposing high amylose starch to chemical treatment (i.e., cross-linking) prior to gelatinization, one skilled in the art would not expect the production of a product exhibiting controlled-release characteristics. Cross-linking of high-amylose starch prior to gelatinization would likely lead to material that would not exhibit controlled release properties, but would resemble an immediate release profile as the cross-linked high amylose starch would be unable to support a matrix capable of controlled release thereby demonstrating essential structural differences between the two cross-linked products. According to Lenaerts et al. (J. Controlled Rel., 1998) such structural differences would lead to an incapacity of the material to have controlled release properties. Jane et al. [Cereal Chemistry, 69(4), 405-409 (1992)] disclose that cross-linking of pregelatinized and dispersed starch causes less difference in the proportion of soluble amylose and amylopectin than did the cross-linking of native granular starch. Jane et al. report no increase in the size of amylose as a result of cross-linking between two or more amylose molecules after the starch had been cross-linked in the granular form and do not mention any controlled release property of the starches cross-linked in the granular form. In addition, Mateescu et al. (U.S. Pat. No. 5,456,921) describe that optimal controlled release is obtained at an amount of cross-linking agent of 7.5 g per 100 g dry starch whereas in the present invention the cross-linking reagent can be added at an amount lower than 0.3 g per 100 g dry starch. This low amount of cross-linking reagent is preferred because it also allows the product to be covered by the monographs for modified food starch of the US Food and Drug Administration and the Food Chemicals Codex as well as the European Parliament and Council Directive Nr/95/2/EC of Feb. 20, 1995 on Food additives other than Colours and Sweeteners (Miscellaneous Directive).
Remarkably, it has been discovered that a novel controlled-released excipient may be prepared in following steps:
(1) granular cross-linking and additionally chemical modification (e.g., hydroxypropylation) of high-amylose starch;
(2) Thermal gelatinization of the starch from step (1); and
(3) Drying the starch from step (2) to yield a powder capable of being used as a controlled release excipient.
The advantages of this excipient include, but are not limited to: (1) ease in processing, (2) avoidance of any organic solvents in the process, (3) ability to obtain high purity products meeting FDA regulations and the Food Chemical Codex as well as the European Parliament and Council Directive Nr 95/2/EC of Feb. 20, 1995 on Food additives other than Colours and Sweeteners (Miscellaneous Directive), (4) the ability to make direct compression tablets, (5) compatibility with hydrophilic and hydrophobic drugs, (6) compatibility with a large range of drug concentrations and solubilities, (7) the safety of cross-linked high amylose starch, (8) an excellent robustness vis-à-vis production and dissolution parameters, (9) an excellent batch-to-batch reproducibility, and (10) a simple and predictable scale-up.
Most particularly, it has been discovered that the controlled release of a drug can be achieved with high-amylose starch that undergoes the sequential transformation described above to produce a powder excipient. Use of this modified starch as a matrix in a tablet produces a remarkable, almost linear release profile and a release time of 2 hours to 24 hours.
It has also been found that this modified starch can be used for the production of implants for local sustained delivery of drugs with an in vivo release extending to periods of 1 to 3 days to 3 to 4 weeks.
In accordance with the invention, there is provided a pharmaceutical formulation comprising a controlled release tablet, further comprising a direct compression blend of a powder of cross-linked and additionally modified high amylose starch as the controlled-release excipient for the drug and powder of at least one drug. The controlled release matrix consists essentially of cross-linked high amylose starch obtained by cross-linking high amylose starch with a suitable cross-linking agent. Additionally, the cross-linked high amylose starch is chemically modified. The sequence of the two reactions (i.e., cross-linking reaction and additional chemical modification) may be performed alternatively in the reverse order or at the same time.
The cross-linked high amylose starch may be obtained with a preferred range of amount of cross-linker between about 0.005 to 0.3 g per 100 g dry starch.
When the pharmaceutical drug(s) used in this invention are very slightly soluble in water, the powder of such drug(s) may represent up to about 70% to about 90% of the weight of the tablet. If the pharmaceutical drug(s) used is highly soluble, it should not exceed about 30% to about 50% of the weight of the tablet.
The tablet according to the invention can also be of the dry coated type. In this case, the core of the tablet contains most of the powder of said drug(s). The outside shell will consist primarily of the controlled release excipient except if special delivery profiles (e.g. Biphasic or double pulse) are necessary.
Thus, the invention as broadly defined provides a process for the manufacture of a novel controlled release excipient consisting mainly of cross-linked high amylose starch for use in the preparation of tablets. Such process comprises:
(a) cross-linking high amylose starch (preferably such high amylose starch contain at least 70% w/w of amylose), preferably with about 0.005 g to about 0.3 g, more preferably about 0.01 g to about 0.12 g, even more preferably about 0.04g to about 0.1 g, most preferably about 0.075 g, cross-linking reagent per 100 g of dry-based high amylose starch in an alkaline aqueous medium at a suitable temperature (preferably about 10xc2x0 C. to about 90xc2x0 C., more preferably about 20xc2x0 C. to about 80xc2x0 C., even more preferably 20xc2x0 C. to about 60xc2x0 C., and most preferably about 30xc2x0 C.), for a suitable reaction time period preferably about 1 minute to about 24 hours, more preferably of about 15 minutes to about 4 hours, even more preferably of about 30 minutes to about 2 hours, and most preferably of about 60 minutes), thereby forming a reaction medium containing a reaction product consisting of a cross-linked high amylose starch slurry (preferably of a concentration of about 5% to about 45%, more preferably of about 20% to about 42%; even more preferably of about 30% to about 40%, and most preferably of about 35%).
(b) subjecting the cross-linked high amylose starch slurry from step (a) to chemical modification (e.g., hydroxypropylation with propylene oxide, preferably about 0.5% to 20%, more preferably about 1 to about 10%, even more preferably of about 3 to 9%, and most preferably of about 6% propylene oxide), at a temperature of about 10xc2x0 C. to about 90xc2x0 C., preferably of about 20xc2x0 C. to about 80xc2x0 C., more preferably of about 20xc2x0 C. to about 50xc2x0 C., and most preferably of about 40xc2x0 C., for a time period of about 1 hour to about 72 hours, preferably of about 2 hours to about 48 hours, more preferably of about 10 hours to about 40 hours, and most preferably for about 29 hours;
Alternatively, steps (a) and (b) are performed in the reverse order or at the same time
(c) neutralizing the reaction medium obtained in step (b) with an acid (preferably a dilute aqueous inorganic acid), washing the slurry formed and optionally dewatering or drying;
(d) forming a slurry at a concentration of about 2% w/w to about 40% w/w, preferably of about 5% w/w to about 35% w/w, more preferably of about 5% w/w to about 25% w/w, and most preferably of about 9% w/w, adjusting the pH to a desired value between 3 and 12 (preferably about 6.0), and gelatinizing the slurry at a temperature of about 80xc2x0 C. to about 180xc2x0 C., preferably of about 120xc2x0 C. to about 170xc2x0 C., more preferably of about 140xc2x0 C. to about 165xc2x0 C., and most preferably of about 160xc2x0 C., for about 1 second to about 120 minutes, preferably of about 30 seconds to about 60 minutes, more preferably of about 1 minute to about 20 minutes, and most preferably of about 8 minutes; and
(e) drying the thermally treated product obtained in step (d) to obtain the controlled release excipient consisting mainly of chemically modified and cross-linked high amylose starch in the form of a powder.